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https://hdl.handle.net/2144/33042

Abstract

Osteosarcoma is the most common primary malignancy of bone in children and young adults, with a worldwide incidence of 3.4 cases per million people per year. For most of the 20th century — before the advent of chemotherapy — osteosarcoma was inevitably fatal. Despite effective local control achieved through highly invasive and ultimately disabling surgical procedures, the vast majority of patients developed pulmonary metastasis and most often died in a matter of months. Fortunately, treatment strategies have evolved tremendously to include multi-agent adjuvant chemotherapy and various forms of limb-sparing surgery that have largely taken the place of amputation. This transformation in therapeutic approach materialized gradually, and became firmly established in practice during the early 1990s. Not surprisingly, it was around that same time that a rather dramatic increase in five-year survival was noted in patients presenting with localized disease — jumping from less than 20% prior to the advent of chemotherapy, to 60-70% following implementation of the current standard of care. However, since this initial period of advancement, very little progress has been made. Systemic treatment strategies have barely evolved over the course of the past two decades, and the probability of long-term survival thus remains largely unchanged. While it is true that roughly two-thirds of patients with localized conventional osteosarcoma survive for at least 5 years after receiving multi-modal therapy, the following fact better reflects the highly-aggressive nature of the disease, and thus also provides a more realistic representation of the long-term prognostic implications with which its typically associated: the risk of recurrence and metastasis remains markedly elevated following complete eradication of the primary tumor. After undergoing surgical resection and multiple rounds of both neoadjuvant and postoperative chemotherapy, a significant quantity of patients thought to be cured see their malignancy recur, spread, and invade distant tissue — at which point, the probability of disease-free survival drops to well below 20%. Thus, the need for enhanced, more precisely-targeted mechanisms of treatment is indisputable. Accordingly, this work will provide an in-depth description of the molecular etiology, pathophysiology, clinical presentation, diagnosis, and treatment of osteosarcoma, while also exploring potentially promising novel therapies aimed to improve patient outcomes.